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Objective: To investigate the efficacy of cholecalciferol (vitamin D3) in raising serum 25-hydroxyvitamin D (25[OH)]D) levels and reducing parathyroid hormone (PTH) levels in patients with chronic kidney disease (CKD).
Methods: In this double-blind, randomized controlled pilot study, participants with CKD stage 3 and 4 (estimated glomerular filtration rate, 15-59 mL/min/1.73 m), vitamin D insufficiency (serum 25[OH]D <30 ng/mL), and serum intact PTH levels >70 pg/mL were randomly assigned to receive either 50 000 IU of cholecalciferol or placebo once weekly for 12 weeks. Primary outcomes (25[OH]D and PTH levels) were measured at baseline, week 6, and week 12. Secondary outcomes (1,25-dihydroxvitamin D and bone turnover markers) were measured at baseline and week 12. Because of skewed data distribution, statistical analyses were performed on a logarithmic scale. The difference between the group means was exponentiated to provide the geometric mean ratio. A linear mixed model using an unstructured variance-covariance matrix was used to examine change in the primary and secondary outcomes over time.
Results: Geometric mean serum 25(OH)D concentrations of the study groups were similar at baseline (P = .77). At week 6, a significant difference between the treatment and placebo groups was detected (P = .001); this difference was maintained at week 12 (P = .002). Among cholecalciferol-treated participants, serum 25(OH)D concentration increased on average from 17.3 ng/mL (95% confidence interval [CI], 11.8-25.2) at baseline to 49.4 ng/mL (95% CI, 33.9-72.0) at week 12. As-treated analysis indicated a trend toward lower PTH levels among cholecalciferol-treated participants (P = .07).
Conclusion: Weekly cholecalciferol supplementation appears to be an effective treatment to correct vitamin D status in patients with CKD.
Vitamin D is an important nutrient for calcium homeostasis and optimal bone health. The main circulating form of vitamin D is 25-hydroxyvitamin D (25[OH]D) (calcidiol), which requires activation by renal 1 α-hydroxylase to form the metabolically active form of vitamin D, 1,25-dihydroxvitamin D (1,25[OH]2D) (calcitriol). Parathyroid hormone (PTH) increases activity of the renal 1 α-hydroxylase in response to low calcium levels. Because chronic kidney disease (CKD) results in decreased kidney mass, there is a compensatory elevation in PTH to maintain adequate blood levels of 1,25(OH)2D for optimal intestinal absorption of calcium. Chronic elevation of PTH, termed secondary hyperparathyroidism, in combination with altered phosphorus metabolism, can lead to renal osteodystrophy and increased mortality due to cardiovascular disease.
Low serum 25(OH)D levels can further exacerbate hyperparathyroidism in patients with CKD. There is an inverse relationship between PTH and 25(OH)D levels in healthy individuals and in patients with CKD. A recent cross-sectional study of patients from geographically diverse regions of the United States has shown that up to 86% of predialysis patients with CKD are vitamin-D insufficient. The National Kidney Foundation guidelines state that optimal 25(OH)D levels should be greater than 30 ng/mL. The National Kidney Foundation recommends correction of vitamin D insufficiency with oral ergocalciferol; however, these recommendations are based on limited prospective clinical trials. Treatment of secondary hyperparathyroidism involves addressing vitamin D status followed by various therapies to reduce PTH levels including calcitriol, vitamin D analogues, calcimimetics such as cinacalcet hydrochloride, or parathyroidectomy. Furthermore, there are no data regarding patients with CKD from studies evaluating the correction of vitamin D insufficiency with cholecalciferol (vitamin D3), which appears to more effectively raise 25(OH)D levels than ergocalciferol (vitamin D2).
We conducted a double-blind, placebo-controlled, 12-week pilot study to evaluate the effectiveness of weekly supplementation with cholecalciferol in reducing PTH levels and correcting vitamin D insufficiency in patients with stage 3 and 4 CKD. Primary endpoints assessed were 25(OH)D and PTH levels. We were interested in determining 25(OH)D and PTH levels over the 12-week period and in analyzing whether changes in these outcomes were dependent on the intervention therapy. For the secondary endpoints, we examined the change from baseline in levels of 1,25(OH)2D and bone turnover markers—bone-specific alkaline phosphatase, C-telopeptide, and tartarate-resistant acid phosphatase isoform 5b (TRAP5b).
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